Margalit Lorber

A study of 20 SLE patients with intravenous immunoglobulin--clinical and serologic response.

Objective: To test the clinical response of systemic lupus erythematosus (SLE) patients to intravenous immunoglobulins (IVIg), and whether the clinical response of IVIg treatment in SLE is accompanied by modification of SLE-associated autoantibodies/antibodies (Abs) and complement levels. Methods: Twenty SLE patients were treated with high-dose (2 g/kg) IVIg monthly, in a 5-d schedule. Each patient received between 1-8 treatment courses. They were evaluated for the clinical response, Systemic Lupus Activity Measure (SLAM) score before and after IVIg, levels of antinuclear antibody (ANA), dsDNA (double-stranded DNA), SS-A or SS-B, ENA (extractable nuclear antigens), C3 and C4 levels before and after the treatment, and before and after each treatment course. Results: A beneficial clinical response following IVIg treatment was noted in 17 out of 20 patients (85%). Few clinical manifestations responded more to treatment: arthritis, fever, thrombocytopenia, and neuropsychiatric lupus. In 9 patients evaluated before and after IVIg, mean SLAM score decreased from 19.3 ± 4.7 to 4 ± 2.9 (P < 0.0001). There was a tendency towards abnormal levels of complement and Abs before IVIg courses among the treatment responders compared with the non-responders, and similarly the former tended to have normalization of their abnormal levels more than the latter. These differences were found statistically significant only with respect to C4 and SS-A or SS-B levels before IVIg courses. Conclusion: IVIg has a high response rate among SLE patients. A combination of clinical manifestations, Abs and complement levels may aid in the future in predicting who among SLE patients will benefit more from IVIg treatment.

Mutation D30N Is Not Preferentially Selected by Human Immunodeficiency Virus Type 1 Subtype C in the Development of Resistance to Nelfinavir

ABSTRACT Differences in baseline polymorphisms between subtypes may result in development of diverse mutational pathways during antiretroviral treatment. We compared drug resistance in patients with human immunodeficiency virus subtype C (referred to herein as “subtype-C-infected patients”) versus subtype-B-infected patients following protease inhibitor (PI) therapy. Genotype, phenotype, and replication capacity (Phenosense; Virologic) were determined. We evaluated 159 subtype-C- and 65 subtype-B-infected patients failing first PI treatment. Following nelfinavir treatment, the unique nelfinavir mutation D30N was substantially less frequent in C (7%) than in B (23%; P = 0.03) while L90M was similar (P < 0.5). Significant differences were found in the rates of M36I (98 and 36%), L63P (35 and 59%), A71V (3 and 32%), V77I (0 and 36%), and I93L (91 and 32%) (0.0001 < P < 0.05) in C and B, respectively. Other mutations were L10I/V, K20R, M46I, V82A/I, I84V, N88D, and N88S. Subtype C samples with mutation D30N showed a 50% inhibitory concentration (IC50) change in susceptibility to nelfinavir only. Other mutations increased IC50 correlates to all PIs. Following accumulation of mutations, replication capacity of the C virus was reduced from 43% ± 22% to 22% ± 15% (P = 0.04). We confirmed the selective nature of the D30N mutation in C, and the broader cross-resistance of other common protease inhibitor mutations. The rates at which these mutational pathways develop differ in C and subtype-B-infected patients failing therapy, possibly due to the differential impact of baseline polymorphisms. Because mutation D30N is not preferentially selected in nelfinavir-treated subtype-C-infected patients, as it is in those infected with subtype B, the consideration of using this drug initially to preserve future protease inhibitor options is less relevant for subtype-C-infected patients.

Genetic variation at NNRTI resistance-associated positions in patients infected with HIV-1 subtype C.

Objective: Genetic differences between subtypes of HIV-1, even when not associated with key resistance mutations, are known to affect baseline susceptibility to specific antiretroviral drugs and resistance-development pathways. We studied the prevalence and patterns of non-nucleoside reverse transcriptase inhibitor (NNRTI)-associated mutations in HIV-1 subtype C-infected patients. Method: We analysed the genetic variation at sites associated with NNRTI and nucleoside reverse transcriptase inhibitor resistance in subtype C- versus B-infected patients, both drug-naive and -experienced. We extended the comparison to subtype B records from the Stanford database. Results: A total of 150 subtype B and 341 subtype C-infected patients were studied. No significant differences were found in treatment and clinical parameters between the groups. In NNRTI-naive patients, changes in NNRTI positions were present in 9.3% of subtype B- versus 33.1% of subtype C-infected patients (P < 0.001). Differences were seen in both drug-naive (subtype B, 10.0% versus subtype C, 50.1%; P < 0.021) and drug-experienced NNRTI-naive patients (subtype B, 9.0% versus subtype C, 23.8%; P < 0.001). In NNRTI experienced patients, the number of A98G/S changes was significantly higher in subtype C patients treated with either efavirenz or nevirapine (P < 0.0001), and V106M was higher in efavirenz-treated subtype C-infected patients (P < 0.0001). The average mutation rates were 1.26 and 1.67 per patient for subtypes B and C, respectively (P = 0.036). The frequency of nucleoside associated mutations, but not M184V, in treated patients was significantly higher in subgroup B-infected patients (P = 0.028). Conclusion: Collectively, these data indicate that genetic variation at NNRTI resistance-associated positions such as V106M and A98S is substantially greater in subtype C-infected patients than in subtype B-infected patients. The natural structure of each subtype probably affects the frequency and pattern of drug resistance mutations selected under treatment.

Antiprothrombin Antibodies are Associated with Pregnancy Loss in Patients with the Antiphospholipid Syndrome

OBJECTIVE: To document the clinical association between the history of pregnancy loss in patients with the diagnosis of primary or secondary antiphospholipid syndrome (APS) and the presence of different antiprothrombin antibody subtypes [immunoglobulin G (IgG), IgM and IgA] in a cohort of patients with APS.

The coexistence of systemic lupus erythematosus with other autoimmune diseases: the kaleidoscope of autoimmunity.

Patients with systemic lupus erythematosis (SLE) often manifest features of other autoimmune diseases. In this review, we provide a detailed compendium of features of SLE that overlap with other conditions. This compendium is important because a critical feature in our understanding of autoimmunity has been the clustering of coexisting/different autoimmune diseases both within an affected patient and within a pedigree. Indeed, autoimmune disorders share a variety of similar clinical and serological defects. For example, all autoimmune disorders are associated with the elaboration of autoantibodies and/or the production of self-reactive mononuclear cell populations; many have high levels of immune complexes and defects in cell-mediated immunity. Several diseases share similar genetic backgrounds, as reflected by study of loci within the major histocompatibility complex. In part the coassociation is due to common genetic tendencies with different environmental precipitating agents (trigger mechanisms). It is likely that many factors can modulate the immune system to autoimmunity in the presence of an appropriate genetic background, eg, drugs, viral infections, UV irradiation, and toxins, ie, toxic oil syndrome and L-tryptophan-induced eosinophilic myalgia. The coexistence of SLE with other autoimmune diseases is an excellent venue to understand these events, and we believe that the presence of other autoimmune diseases in patients with SLE can be called the kaleidoscope of autoimmunity.

Prevention of fetal loss in experimental antiphospholipid syndrome by low-molecular-weight heparin

OBJECTIVE The purpose of this study was to compare the effectiveness of low-molecular-weight heparin with regular heparin in the prevention of fetal resorption in mice with the antiphospholipid syndrome. STUDY DESIGN Antiphospholipid syndrome was passively induced in ICR mice by injecting them with anticardiolipin antibodies on the first day of pregnancy. Subsequently, these mice were treated with low-molecular-weight heparin in two different doses, with regular heparin, and with a placebo. On gestational day 17 the mice were killed by cervical dislocation, and the pregnancy outcome was evaluated. Statistical analysis was performed by means of a one-way analysis of variance using Bonferronis t test. RESULTS Treatment with low-molecular-weight heparin resulted in a resorption rate of 22.4% as opposed to 41.4% in mice with antiphospholipid syndrome that were given regular heparin and 51.7% in nontreated controls. CONCLUSION We conclude that low-molecular-weight heparin can prevent fetal resorptions in mice with antiphospholipid syndrome.

Oxidized low-density lipoprotein (Ox-LDL) but not LDL aggravates the manifestations of experimental antiphospholipid syndrome (APS)

Ox‐LDL is thought to play a major role in atherogenesis. The mechanisms mediating the deleterious influences of Ox‐LDL include foam cell formation and cell cytotoxicity. The production of anti‐Ox‐LDL antibodies results in the formation of immune complexes which are taken up at enhanced rate by macrophages, leading to foam cell formation. APS is characterized by repeated venous and arterial thromboembolic phenomena, recurrent fetal loss and thrombocytopenia, associated with the presence of antibodies to negatively charged phospholipids (aPL) (i.e. cardiolipin, phosphatidylserine). Phospholipids bear structural resemblance to LDL, and several studies have indeed proved that aPL display cross‐reactivity with anti‐Ox‐LDL antibodies. In this study we assessed the capacity of oxidized and native forms of LDL to aggravate the clinical picture of experimentally induced APS in naive mice. Mice were actively immunized intradermally with anticardiolipin antibodies and developed a clinical picture resembling APS in humans. Subsequently, the mice were infused with either Ox‐LDL, native LDL or PBS, and similar regimens were applied to controls. APS mice infused with Ox‐LDL were found to exhibit a significantly more severe form of the disease in comparison with native LDL‐ and PBS‐infused mice, expressed by lower platelet counts (261 000/mm3, 535 000/mm3 and 455 000/mm3, respectively), longer activated partial thromboplastin time (aPTT) (99 ± 12 s, 63 ± 8 s and 74 ± 8 s, respectively) and higher fetal resorption rates (72.7%, 34.4% and 32.6%, respectively). The results of this study show that Ox‐LDL, compared with native LDL, aggravates the clinical manifestations of experimental APS and suggest that cross‐reactivity of Ox‐LDL with phospholipids may provide a pathogenic explanation for this effect.

Inhibitor(s) of natural anti-cardiolipin autoantibodies

IgG fractions were purified on Sepharosc anti‐human IgG column from eight sera of healthy donors, having no anti‐cardiolipin (aCL) activity as measured by anti‐cardiolipin ELISA assay (aCL‐ELISA). All the IgG fractions, after elution with 4.9 m MgCl2, reacted with CL. The antigen‐binding characteristics of the IgG fractions purified from normal human serum (NHS) were similar to those of IgG fractions purified from sera of four patients with the anti‐phospholipid syndrome (APLS). Competition assay confirmed the specificity of the binding of the purified IgG fractions to CL. The same results have been achieved with IgG fractions purified on Sepharose Protein‐A column. The binding to CL was completely inhibited by either whole NHS and sera from various animal species, or by β2‐glycoprotein I (β2‐GPI). Our results support the notion of the existence of both natural anti‐CL antibodies and serum inhibitor(s) in sera of healthy individuals. It is conceivable that in part the pathogenesis of APLS entails defects in the natural inhibitors of aCL antibodies.

Systemic lupus erythematosus and thymoma--a double-edged sword.

The coexistence of systemic lupus erythematosus (SLE) and thymoma is rare. We describe 2 female patients with this combination. A 48-year-old woman presented with dyspnea due to a left pleural effusion. Her past history revealed over the previous 3 years the development of anemia, thrombocytopenia, alopecia, pericardial effusion and proteinuria. Four months prior to this hospitalization, the patient was first admitted due to purpura. At that time, laboratory tests revealed an elevated sedimentation rate, elevated titers of ANA and anti-DNA. Chest X-ray demonstrated a widened mediastinum, and upon operation an encapsulated thymoma was excised. Four months following the thymectomy, the patient is unresponsive despite high dose steroid therapy. Another patient, a 30-year-old woman, presented with SLE (cutaneous, arthritis, anemia, positive ANA and high titers of anti-DNA) and thymoma simultaneously. Six years after thymectomy the patient is in SLE remission. Thymectomy in mice prone to autoimmunity (NZB/W mice) has been shown to accelerate the autoimmune manifestations. Conversely, the opposite effect is seen in MRL/lpr mice. The immunological effect of adult thymectomy on the course of human SLE remains to be established, on a larger series of patients. It seems that the heterogenicity of human patients is exemplified by the contrasting effects of thymectomy for thymoma in SLE patients.

Anticardiolipin Antibodies in Behçet's Disease

Twenty‐six patients with Behçets disease were studied for serum levels of anticardiolipin (ACL) antibody isotypes IgG and IgM. The frequency of elevated levels of ACL antibody isotype IgM was found to be significantly increased in these patients. This increased frequency, however, did not correlate statistically with a thrombotic tendency, colchicine intake, antinuclear antibodies, or a positive VDRL test.